rs80338827
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002473.6(MYH9):c.2105G>A(p.Arg702His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R702C) has been classified as Pathogenic.
Frequency
Consequence
NM_002473.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH9 | NM_002473.6 | c.2105G>A | p.Arg702His | missense_variant | 17/41 | ENST00000216181.11 | NP_002464.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH9 | ENST00000216181.11 | c.2105G>A | p.Arg702His | missense_variant | 17/41 | 1 | NM_002473.6 | ENSP00000216181 | P1 | |
MYH9 | ENST00000685801.1 | c.2168G>A | p.Arg723His | missense_variant | 18/42 | ENSP00000510688 | ||||
MYH9 | ENST00000687922.1 | n.441G>A | non_coding_transcript_exon_variant | 3/3 | ||||||
MYH9 | ENST00000691109.1 | n.2400G>A | non_coding_transcript_exon_variant | 11/35 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | Associated with most severe phenotype - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014081). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). Different missense changes at the same codon (p.Arg702Cys, p.Arg702Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014078, VCV000627035). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Sep 22, 2024 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH9 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 14081). This missense change has been observed in individual(s) with MYH9-related disease (PMID: 11590545, 11935325, 26387855). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the MYH9 protein (p.Arg702His). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31064749, 23207509, 16098078, 26226608, 37201161, 31328266, 34383333, 24186861, 37752057, 25077172, 30103613, 22558294, 24165359, 37733142, 23223919, 11590545, 20200500, 26387855, 30916803, 17241369, 35530141, 11935325, 32980210) - |
MYH9-related disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.2105G>A;p.(Arg702His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 14081; PMID: 31064749; PMID: 11935325; PMID: 11590545) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Myosin_head) - PM1. This variant is not present in population databases (rs80338827- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 11935325) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at